Results from preclinical studies with 2F8, a murine analog of TRX518 (Tolerx, Inc) a first-in-class immunomodulatory agent currently in a Phase I clinical study for the treatment of cancer, was presented today by Tolerx, a biopharmaceutical company developing novel therapies to treat cancer by normalizing the immune response.

TRX518 is an investigational immunotherapy designed to activate GITR (glucocorticoid-induced tumor necrosis factor receptor) found on multiple types of T cells and other immune cells. GITR plays a role in directing the anti-tumor immune response via a multifaceted mechanism of action that includes activating tumor antigen-specific T effector cells, abrogating the suppression induced by T regulatory cells, and activating NK cells. In preclinical studies, TRX518 achieved its effect without compromising normal immune function, and preclinical models suggest TRX518 to have a favorable safety profile. A Phase I clinical study of TRX518, a first-in-class anti-GITR monoclonal antibody, has been initiated to assess the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of ascending single doses in patients with malignant melanoma. TRX518 is designed to have activating and sustaining effects on T lymphocytes and other cells for enhancing the immune system’s responses against cancer cells, including responses that may occur with TRX518 alone, as well as complementary responses in combination with other cancer therapies including cancer vaccines.

Preclinical data demonstrated anti-tumor efficacy in a murine model as a monotherapy, and further enhanced efficacy when used in combination with multiple classes of chemotherapeutics and with biologic agents such as anti-CTLA4. Both TRX518, and its murine analog, 2F8, are monoclonal antibodies reactive with the GITR and are designed to enhance the immune system’s anti-tumor response by enabling T lymphocytes and other cells to more effectively attack cancer cells. The preclinical data were presented as a poster and invited talk at the Keystone Symposia “Immunoregulatory Networks” meeting held in Breckenridge, Colorado.

“These data underscore the exciting promise of our anti-GITR program, highlighting the potential efficacy of TRX518’s unique and powerful mechanism of action,” said Tony deFougerolles, Tolerx’s Chief Scientific Officer. “The preclinical data suggest that anti-GITR may have similar efficacy to anti-CTLA4, and that the combination of anti-GITR with anti-CTLA4 and chemotherapy may result in dramatic regression of established tumors.”

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The preclinical studies included combinations of an anti-GITR monoclonal antibody, chemotherapeutic drugs (including gemcitabine, cyclophosphamide, 5-fluorouracil, and doxorubicin), and an anti-CTLA4 monoclonal antibody. These agents were evaluated for their anti-tumor efficacy against established tumors using a colon carcinoma model in mice. Results and data included:
– The combination of anti-GITR and chemotherapeutic drugs showed potent anti-tumor activity against established tumors and were efficacious across multiple classes of drugs including alkylating agents, DNA intercalators, and pyrimidine analogs.
– The combination of anti-GITR and gemcitabine showed anti-tumor activity against established tumors comparable to a combination consisting of anti-CTLA4 and gemcitabine.
– The use of a triple combination (anti-GITR, anti-CTLA4, and gemcitabine) demonstrated the greatest anti-tumor results, with complete tumor regression observed in greater than 73% of mice (P<0.01).

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A Phase I, first-in-human, open label, dose escalation safety study of TRX518 in adults with Stage III/IV metastatic melanoma was initiated in December 2010 and is currently underway.


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